Phase 1
Phase 2
Phase 3
Application
Therapeutic
area
Cardiovascular-
Metabolics
Oncology
Others

Edoxaban (JP)
(DU-176b / AF / FXa inhibitor)

Prasugrel (JP)
(CS-747 / Ischemic stroke / Anti-
platelet agent)

Esaxerenone (JP)
(CS-3150 / Hypertension /
MR antagonist)

Edoxaban (ASCA etc.)
(DU-176b / AF / FXa inhibitor)

Edoxaban (ASCA etc.)
(DU-176b / VTE / FXa inhibitor)

Tivantinib (US/EU)
(ARQ 197 / HCC / MET inhibitor)

Denosumab (JP)
(AMG 162 / Breast cancer adjuvant /
Anti-RANKL antibody)

Nimotuzumab (JP)
(DE-766 / Gastric cancer / Anti-EGFR
antibody)

Vemurafenib (US/EU)
(PLX4032 / Melanoma Adjuvant / BRAF
inhibitor)

Quizartinib (US/EU/Asia)
(AC220 / AML-2
nd
/ FLT3-ITD inhibitor)

Quizartinib (US/EU/Asia)
(AC220 / AML-1
st
/ FLT3-ITD inhibitor)

Pexidartinib (US/EU)
(PLX3397 / TGCT / CSF-1R/KIT/FLT3-ITD
inhibitor)

Laninamivir (US/EU)
(CS-8958 / Anti-influenza /
out-licensing with Biota)

Mirogabalin (US/EU)
(DS-5565 / Fibromyalgia / α2δ ligand)

Mirogabalin (JP/Asia)
(DS-5565 / DPNP/ α2δ ligand)

Mirogabalin (JP/Asia)
(DS-5565 / PHN / α2δ ligand)

Hydromorphone (JP)
(DS-7113 / Cancer pain / Opioid μ-
receptor regulator)

CHS-0214 (JP)
(Etanercept BS / Rheumatoid
arthritis / TNFα inhibitor)

VN-0105 (JP)
(DPT-IPV / Hib vaccine)

Laninamivir (JP)
(CS-8958 / Anti-influenza / nebulizer)

Esaxerenone (JP)
(CS-3150 / DM nephropathy / MR
antagonist)

DS-8500 (JP/US)
(Diabetes / GPR119 agonist)

Patritumab (EU)
(U3-1287 / Anti-HER3 antibody)

Pexidartinib (US)
(PLX3397 / CSF-1R/KIT/FLT3-ITD
inhibitor)

DS-1647 (JP)
(Glioblastoma / G47Δ virus)

DS-1040
(Acute ischemic stroke / TAFIa inhibitor)

DS-2330
(Hyperphosphatemia)

DS-9231/TS23
(Thrombosis / α2-PI inactivating antibody)

DS-9001
(Dyslipidemia / Anti-PCSK9 Anticalin-Albumod)

DS-3032 (US/JP)
(MDM2 inhibitor)

PLX7486 (US)
(FMS / TRK inhibitor)

PLX8394 (US)
(BRAF inhibitor)

DS-6051 (US/JP)
(NTRK/ROS1 inhibitor)

PLX9486 (US)
(KIT inhibitor)

DS-3201 (JP)
(EZH1/2 inhibitor)

PLX73086 (US)
(CSF-1R inhibitor)

PLX51107 (US)
(BRD4 inhibitor)

DS-1971
(Chronic pain)

DS-1501
(Osteoporosis / Anti-Siglec-15 antibody)

DS-7080 (US)
(AMD / Angiogenesis inhibitor)

DS-2969
(
Clostridium difficile
infection
/GyrB inhibitor)

DS-5141 (JP)
(DMD / ENA oligonucleotide)

VN-0102/JVC-001 (JP)
(MMR vaccine)

Hydromorphone (JP)
(DS-7113 / Cancer pain / Opioid μ-
receptor agonist)

CL-108 (US)
(Acute pain / Opioid μ-receptor
agonist)

Intradermal Seasonal
Influenza Vaccine (JP)
(VN-100 / prefilled i.d. vaccine for
seasonal flu)

VN-0107/MEDI3250 (JP)
(Nasal spray flu vaccine)

Denosumab (JP)
(AMG 162 / Rheumatoid arthritis /
Anti-RANKL antibody)
Major R&D Pipeline

DS-8895 (JP)
(Anti-EPHA2 antibody)

DS-8273 (US)
(Anti-DR5 antibody)

DS-5573 (JP)
(Anti-B7-H3 antibody)

DS-8201 (JP/US)
(Anti-HER2 ADC)

U3-1784 (EU)
(Anti-FGFR4 antibody)

DS-1123 (JP)
(Anti-FGFR2 antibody)

U3-1402 (JP)
(Anti-HER3 ADC)
As of January 2017
Red: Major changes after the FY2016 Q2 financial announcement on October 31, 2016
11. Major R&D Pipeline (Innovative pharmaceuticals
）
◆
Oncology (Late-stage pipeline products)
Generic Name/Project Code Number
(Brand Name)
Class
Target indication
Region Stage
Dosage
Form
Partner
Target FY for
approval/launch
Anti-RANKL antibody
Breast cancer adjuvant
JP
P3 Injection
Amgen
2020
BRAF inhibitor
Melanoma adjuvant
US/EU
P3
Oral
–
–
MET inhibitor
Hepatocellular cancer
US/EU
P3
Oral
ArQule, Inc.
2018
US/EU/Asia P3
2018
US/EU/Asia P3
2021-
JP
P1
–
Tenosynovial Giant Cell Tumor (TGCT)
US/EU
P3
2019
Solid tumor
Asia
P1
–
Glioblastoma
US
P2
–
c-KIT Melanoma
Asia
P1/2
–
Melanoma, solid tumor
US
P1/2
Merck & Co., Inc.
–
Anti-EGFR antibody
Gastric cancer
JP
P3 Injection InnoClMAb Pte Ltd
2020
Anti-HER3 antibody
Head & neck cancer
EU
P2 Injection
–
–
Oncolytic HSV-1
Glioblastoma
JP
P2 Injection
ActiVec Inc.
–
Remarks
Denosumab/AMG 162
Ranmark (JP)
Additional indication
The fully human monoclonal antibody to target RANK Ligand, an essential mediator of osteoclast formation.
Vemurafenib/PLX4032
Zelboraf
Additional indication. Licensee Roche is conducting the
study. Submission in 2017 is planned.
The molecular-targeted agent to inhibit BRAF V600E mutation.
Tivantinib/ARQ 197
HCC with MET high patients
The molecular-targeted agent to inhibit HGF(hepatocyte growth factor) receptor, MET which has multiple roles in intracellular signal transductions such as cancer cell proliferation, angiogenesis, invasion, and apoptosis
induction.
Nimotuzumab/DE-766
Patritumab/U3-1287
Pexidartinib/PLX3397
CSF-1R/KIT/FLT3-ITD inhibitor
Oral
–
Quizartinib/AC220
FLT3-ITD inhibitor
Acute myeloid leukemia
Oral
–
Relapsed and refractory AML patients
Newly diagnosed AML patients
Kinase inhibitor against a receptor-type tyrosine kinase, FLT3. Therapeutic effect for patients with acute myeloid leukemia harboring FLT3-ITD mutation is expected.
DS-1647(G47
D
)
Received SAKIGAKE Designation from MHLW
Investigator Initiated Study is on-going
The third generation oncolytic herpes simplex virus type 1(HSV-1), ghenetically-engineered to restrict virus replication to tumor cells. This oncolytic virus therapy is expected equal or better safety and better efficacy profile
compare to existing oncolytic virus.
Underline: change after FY2016 Q2 Financial Announcement in October 2016
As of January 2017
The humanized monoclonal antibody to target Epidermal Growth Factor Receptor(EGFR). This antibody is expected to be a best in class EGFR, safety against the skin toxicity and the efficacy comparable to the other
antibodies.
The fully human monoclonal antibody to target HER3, one of the Epidermal Growth Factor Receptor (EGFR) family of proteins. HER 3 is overexpressed in many tumors of epithelial origin and HER2/HER3 dimers and
EGFR/HER3 dimers are expected more potent to induce tumor cell proliferation than homodimers of HER2 or EGFR.
Including pigmented villonodular synovitis
Including TGCT
Combination with pembrolizumab in collaboration with
Merck
The molecular-targeted agent to inhibit CSF-1R, KIT and FLT3-ITD. This agent is expected to reduce tumor cell proliferation and expansion of metastases.

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On January 31, 2017 NanoString Technologies, Inc. (NASDAQ:NSTG), a provider of life science tools for translational research and molecular diagnostic products, reported that Humana has issued a positive coverage decision for the Prosigna Breast Cancer Gene Signature Assay (Press release, NanoString Technologies, JAN 31, 2017, View Source [SID1234517618]). Humana and its more than 13 million members join other payors now covering Prosigna, collectively representing more than 175 million covered lives throughout the United States.

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This positive coverage decision is in line with updated ASCO (Free ASCO Whitepaper) guidelines released in February of 2016, wherein Prosigna is considered medically necessary to assess the necessity of adjuvant chemotherapy in ER-positive, HER2-negative, node-negative breast cancer patients, when adjuvant chemotherapy is not precluded due to any other factor.

"Coverage by Humana is another important milestone in making our Prosigna test available to all indicated patients," said Brad Gray, president and chief executive officer of NanoString Technologies. "Our team has done an outstanding job of working with both national and regional payors to ensure that their patients have access to this state-of-the-art test."

The updated healthcare policy for Humana, which now includes the Prosigna Assay, is available on its website:
View Source;searchtype=freetext&policyType=both

About the Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Dx Analysis System
The Prosigna Assay provides a risk category and numerical score for assessment of the risk of distant recurrence of disease at 10 years in postmenopausal women with node-negative (Stage I or II) or node-positive (Stage II), hormone receptor-positive (HR+) breast cancer. Based on the PAM50 gene signature initially discovered by Charles Perou, Ph.D. and colleagues, the Prosigna Assay is an in vitro diagnostic tool that utilizes gene expression data weighted together with clinical variables to generate a risk category and numerical score to assess a patient’s risk of distant recurrence of disease. The Prosigna Assay measures gene expression levels of RNA extracted from formalin-fixed paraffin embedded (FFPE) breast tumor tissue previously diagnosed as invasive breast carcinoma.

The Prosigna Assay requires minimal hands-on time and runs on NanoString’s proprietary nCounter Dx Analysis System, which offers a reproducible and cost-effective way to profile many genes simultaneously with high sensitivity and precision.

The nCounter Dx Analysis System is a highly automated and easy-to-use platform that utilizes a novel digital barcoding chemistry to deliver high precision multiplexed assays. The system is available in the multi-mode FLEX configuration, which is designed to meet the needs of high-complexity clinical laboratories seeking a single platform with the flexibility to run the Prosigna Breast Cancer Assay and, when operated in the "Life Sciences" mode, process translational research experiments and multiplexed assays developed by the laboratory.

In the United States, the Prosigna Assay is 510(k) cleared for use on the nCounter Dx Analysis System, and is available for diagnostic use when ordered by a physician. The Prosigna Assay has been CE-marked and is available for use by healthcare professionals in the European Union and other countries that recognize the CE Mark, as well as Canada, Israel, Australia, New Zealand and Hong Kong. In the U.S., the Prosigna Assay is indicated in female breast cancer patients who have undergone surgery in conjunction with locoregional treatment consistent with standard of care, either as:

(1) a prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-negative, Stage I or II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors or (2) a prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-positive (1-3 nodes), Stage II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors. The device is not intended for patients with four or more positive nodes.

For more information, please visit www.prosigna.com.

On January 31, 2017 Thermo Fisher Scientific Inc. (NYSE: TMO), the world leader in serving science, reported its financial results for the fourth quarter and full year ended December 31, 2016 (Press release, Thermo Fisher Scientific, JAN 31, 2017, View Source [SID1234517606]).

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Fourth Quarter and Full Year 2016 Highlights

Fourth quarter revenue increased 6% to $4.95 billion.
Full year revenue grew 8% to $18.27 billion.
Fourth quarter GAAP diluted earnings per share (EPS) increased 6% to $1.59.
Fourth quarter adjusted EPS grew 14% to $2.41.
Full year GAAP diluted EPS increased 3% to $5.09.
Full year adjusted EPS grew 12% to $8.27.
Invested more than $750 million in R&D in 2016, and launched significant new products, including Q Exactive BioPharma mass spectrometry and Integrion chromatography systems, TSX laboratory freezers, Ion Torrent cancer assays, and new tests for drugs-of-abuse and autoimmune disease.
Strengthened capabilities in Shanghai, Seoul and Singapore during the year to build on industry-leading presence in Asia-Pacific and emerging markets and continued to deliver strong growth in the region, led by outstanding performance in China.
Deployed approximately $7 billion of capital in 2016, with $5.5 billion spent on strategic acquisitions, including FEI Company and Affymetrix, and $1.5 billion returned to shareholders through a combination of stock buybacks and dividends.
Adjusted EPS, adjusted operating income, adjusted operating margin and free cash flow are non-GAAP measures that exclude certain items detailed later in this press release under the heading "Use of Non-GAAP Financial Measures."

"I’m pleased to report that we achieved the goals we laid out for 2016, and successfully executed our strategy to deliver another excellent year," said Marc N. Casper, president and chief executive officer of Thermo Fisher Scientific.

"We effectively deployed the largest R&D budget in our industry, and launched new high-impact products across all of our technology platforms. In Asia-Pacific and emerging markets, we leveraged our industry-leading scale to drive strong growth, especially in China, where we’re capturing opportunities aligned with the new five-year plan.

"We also continued to successfully execute our capital deployment strategy to create value for our shareholders. I’m really excited about our acquisition of FEI – the third largest in our history – and look forward to the opportunities we have to leverage these complementary technologies to drive growth.

"To sum it up, with a strong 2016 behind us, we’re positioned for another great year ahead."

Fourth Quarter 2016

As previously communicated, the company’s 2016 fiscal calendar had four fewer selling days in the fourth quarter versus the fourth quarter of 2015. Consequently, revenue and organic growth results in the 2016 quarter were negatively affected by the fewer days, and operating margin benefited due to fewer days of costs. Revenue for the quarter grew 6% to $4.95 billion in 2016, versus $4.65 billion in 2015. Organic revenue growth was essentially flat; acquisitions increased revenue by 8% and currency translation reduced revenue by 1%.

GAAP Earnings Results

GAAP diluted EPS in the fourth quarter increased to $1.59, versus $1.50 in the same quarter last year. GAAP operating income for the fourth quarter of 2016 grew to $753 million, compared with $690 million in the fourth quarter of 2015. GAAP operating margin increased to 15.2%, compared with 14.8% in the fourth quarter of 2015.

Non-GAAP Earnings Results

Adjusted EPS in the fourth quarter of 2016 rose 14% to $2.41, versus $2.12 in the fourth quarter of 2015. Adjusted operating income for the fourth quarter of 2016 grew 14% compared with the year-ago quarter. Adjusted operating margin expanded 160 basis points to 24.8%, compared with 23.2% in the fourth quarter of 2015.

Full Year 2016

Revenue for the full year grew 8% to $18.27 billion in 2016, versus $16.97 billion in 2015. Organic revenue growth was 4%; acquisitions increased revenue by 4% and currency translation reduced revenue by 1%.

GAAP Earnings Results

GAAP diluted EPS for the full year increased to $5.09, versus $4.92 in 2015. GAAP operating income for 2016 grew to $2.45 billion, compared with $2.34 billion a year ago. GAAP operating margin was 13.4% in 2016, compared with 13.8% in 2015. GAAP operating results reflect acquisition-related charges in the 2016 period.

Non-GAAP Earnings Results

Adjusted EPS for the full year rose 12% to $8.27, versus $7.39 in 2015. Adjusted operating income for 2016 grew 10% compared with 2015, and adjusted operating margin expanded 60 basis points to 23.1%, compared with 22.5% a year ago.

Annual Guidance for 2017

The company will provide 2017 financial guidance on its earnings conference call this morning at 8:30 a.m. Eastern time.

Segment Results

Management uses adjusted operating results to monitor and evaluate performance of the company’s four business segments, as highlighted below. Since these results are used for this purpose, they are also considered to be prepared in accordance with GAAP.

Fourth quarter revenue results were negatively affected by the four fewer selling days in 2016 and fourth quarter operating margin benefited from fewer days of costs. Fourth quarter and full year results were negatively affected by the impact of foreign currency exchange rates. The impact of the fewer days in the fourth quarter and foreign exchange affects each of the segments to varying degrees.

Life Sciences Solutions Segment

In the fourth quarter of 2016, Life Sciences Solutions Segment revenue grew 10% to $1.34 billion, compared with revenue of $1.21 billion in the fourth quarter of 2015. Segment adjusted operating margin increased to 33.3%, versus 31.6% in the 2015 quarter.

For the full year 2016, Life Sciences Solutions Segment revenue rose 12% to $4.98 billion, compared with revenue of $4.44 billion in 2015. Segment adjusted operating margin increased to 30.4% in 2016, compared with 30.1% a year ago.

Analytical Instruments Segment

Analytical Instruments Segment revenue grew 32% to $1.22 billion in the fourth quarter of 2016, compared with revenue of $925 million in the fourth quarter of 2015. Segment adjusted operating margin increased to 24.5%, versus 22.1% in the 2015 quarter.

For the full year 2016, Analytical Instruments Segment revenue rose 14% to $3.67 billion, compared with revenue of $3.21 billion in 2015. Segment adjusted operating margin grew to 20.3%, versus 19.1% in 2015.

Specialty Diagnostics Segment

Specialty Diagnostics Segment revenue in the fourth quarter was $834 million in 2016, compared with revenue of $865 million in the fourth quarter of 2015. Segment adjusted operating margin increased to 27.2%, versus 26.2% in the 2015 quarter.

For the full year 2016, Specialty Diagnostics Segment revenue grew 3% to $3.34 billion, compared with revenue of $3.24 billion in 2015. Segment adjusted operating margin increased to 27.2%, versus 2015 results of 26.9%.

Laboratory Products and Services Segment

In the fourth quarter of 2016, Laboratory Products and Services Segment revenue was $1.76 billion, compared with revenue of $1.82 billion in the fourth quarter of 2015. Segment adjusted operating margin was 14.6%, versus 14.7% in the 2015 quarter.

For the full year 2016, Laboratory Products and Services Segment revenue grew 6% to $7.03 billion, compared with revenue of $6.66 billion in 2015. Segment adjusted operating margin was 15.0% in both periods.

Use of Non-GAAP Financial Measures

In addition to the financial measures prepared in accordance with generally accepted accounting principles (GAAP), we use certain non-GAAP financial measures, including adjusted EPS, adjusted operating income and adjusted operating margin, which exclude certain acquisition-related costs, including charges for the sale of inventories revalued at the date of acquisition and significant transaction costs; restructuring and other costs/income; and amortization of acquisition-related intangible assets. Adjusted EPS also excludes certain other gains and losses that are either isolated or cannot be expected to occur again with any regularity or predictability, tax provisions/benefits related to the previous items, benefits from tax credit carryforwards, the impact of significant tax audits or events and the results of discontinued operations. We exclude the above items because they are outside of our normal operations and/or, in certain cases, are difficult to forecast accurately for future periods. We also use a non-GAAP measure, free cash flow, which is operating cash flow, net of capital expenditures, and also excludes operating cash flows from discontinued operations to provide a view of the continuing operations’ ability to generate cash for use in acquisitions and other investing and financing activities. We believe that the use of non-GAAP measures helps investors to gain a better understanding of our core operating results and future prospects, consistent with how management measures and forecasts the company’s performance, especially when comparing such results to previous periods or forecasts.

For example:

We exclude costs and tax effects associated with restructuring activities, such as reducing overhead and consolidating facilities. We believe that the costs related to these restructuring activities are not indicative of our normal operating costs.

We exclude certain acquisition-related costs, including charges for the sale of inventories revalued at the date of acquisition and significant transaction costs. We exclude these costs because we do not believe they are indicative of our normal operating costs.

We exclude the expense and tax effects associated with the amortization of acquisition-related intangible assets because a significant portion of the purchase price for acquisitions may be allocated to intangible assets that have lives of 5 to 20 years. In 2017, based on acquisitions closed through the end of 2016, our adjusted EPS will exclude approximately $2.53 of expense for the amortization of acquisition-related intangible assets. Exclusion of the amortization expense allows comparisons of operating results that are consistent over time for both our newly acquired and long-held businesses and with both acquisitive and non-acquisitive peer companies.

We also exclude certain gains/losses and related tax effects, benefits from tax credit carryforwards and the impact of significant tax audits or events (such as the effect on deferred tax balances of enacted changes in tax rates), which are either isolated or cannot be expected to occur again with any predictability and that we believe are not indicative of our normal operating gains and losses. For example, we exclude gains/losses from items such as the sale of a business or real estate, gains or losses on significant litigation-related matters, gains on curtailments of pension plans, the early retirement of debt and discontinued operations.

We also report free cash flow, which is operating cash flow, net of capital expenditures, and also excludes operating cash flows from discontinued operations to provide a view of the continuing operations’ ability to generate cash for use in acquisitions and other investing and financing activities.

Thermo Fisher’s management uses these non-GAAP measures, in addition to GAAP financial measures, as the basis for measuring the company’s core operating performance and comparing such performance to that of prior periods and to the performance of our competitors. Such measures are also used by management in their financial and operating decision-making and for compensation purposes.

The non-GAAP financial measures of Thermo Fisher’s results of operations and cash flows included in this press release are not meant to be considered superior to or a substitute for Thermo Fisher’s results of operations prepared in accordance with GAAP. Reconciliations of such non-GAAP financial measures to the most directly comparable GAAP financial measures are set forth in the accompanying tables. Thermo Fisher does not provide GAAP financial measures on a forward-looking basis because we are unable to predict with reasonable certainty and without unreasonable effort items such as the timing and amount of future restructuring actions and acquisition-related charges as well as gains or losses from sales of real estate and businesses, the early retirement of debt and the outcome of legal proceedings. The timing and amount of these items are uncertain and could be material to Thermo Fisher’s results computed in accordance with GAAP.

On January 31, 2017 Kyowa Hakko Kirin Co., Ltd. (Headquarters: Chiyoda-ku, Tokyo; President and CEO: Nobuo Hanai, hereinafter, "Kyowa Hakko Kirin"), reported that it has established Kyowa Kirin Frontier Co., Ltd. (hereinafter, "Kyowa Kirin Frontier") on January 18, 2017 as part of "CSV(Note 1) management based on our unique business structure," one of the core strategies set forth by Kyowa Hakko Kirin in its current Mid-term Business Plan (Press release, Kyowa Hakko Kirin, JAN 31, 2017, View Source [SID1234517604]).

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Kyowa Kirin Frontier will work toward obtaining approval to manufacture and market "Authorized version (Note 2)" of NESP, a core product of Kyowa Hakko Kirin, in Japan. Through such efforts by Kyowa Kirin Frontier, it will be possible to respond to the changes in the social environment surrounding healthcare in Japan and the diversification of the needs thereof, and to meet social demands for medical cost containment.

The Kyowa Hakko Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies. Note 1: CSV stands for "Creating Shared Value." It ref

On January 31, 2018 SignalRx Pharmaceuticals Inc., a clinical-stage company focused on developing new and more effective oncology drugs with designed multiple target-selected inhibition profiles, reported the publication of key research in the journal Proceedings of the National Academy of Sciences (doi: 10.1073/pnas.1613091114 PNAS January 30, 2017) (Press release, SignalRx, JAN 31, 2017, http://www.ireachcontent.com/news-releases/signalrx-pharmaceuticals-announces-breakthrough-results-on-novel-anti-cancer-dual-pi3k-brd4-inhibition-paradigm-in-pnas-publication-612341103.html [SID1234527325]).

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SignalRx Pharmaceuticals Inc., in collaboration with researchers at the University of California, San Diego School of Medicine and Moores Cancer Center, led by Dr. Donald L. Durden, Professor and Associate Director of Pediatric Oncology at the Moores UCSD Cancer Center, and senior scientific advisor at SignalRx along with Dr. Tatiana Kutateladze, Professor at the University Colorado, Department of Pharmacology, report on key preclinical findings using the small molecule SF2523 designed to inhibit the key cancer targets PI3K and BRD4.

Key results include:

Designed dual inhibition: The dual inhibitor SF2523 inhibits the acetyl-lysine binding of the epigenetic reader protein BRD4 as well the kinase activity of PI3K thus simultaneously disrupting two orthogonal cancer driving mechanisms that promote undesirable effects from the oncogene MYC which is responsible for activating the immuno-oncology targets CD47 and PD-L1. X-ray crystal structures of SF2523 bound to BRD4 isoforms were obtained and are consistent with in silico modeling predictions and thus provide insights for further investigations.
Mode of action: SF2523 blocks both PI3K and BRD4 signaling in vitro and in vivo promoting maximal MYC down-regulation.
Anticancer activity in vivo: SF2523 markedly inhibits cancer cell growth and metastasis in mouse models of neuroblastoma and an orthotopic pancreatic metastatic tumor model.
Safe in vivo profile: Most importantly, the dual PI3K/BRD4 inhibitor SF2523 is dramatically much safer in vivo than the administration of two separate inhibitors in combination (PI3K and BRD4). This proof of concept shows that designing 1 drug with the attributes of 2 distinct drugs (2 drugs in 1) can eliminate or significantly reduce unwanted added toxicity of combination drugs providing an exciting opportunity for the exploration of more sophisticated combinations for maximal anticancer efficacy.
SF2523, as discussed in the manuscript, inhibits phosphatidylinositol 3-kinase (PI3K) which, in addition to drive cancer on its own, also inhibits the epigenetic reader bromodomain-containing protein 4 (BRD4). This new anticancer paradigm harnesses the synergistic impact of inhibiting simultaneously PI3K and BRD4 to maximally inhibit MYC activity by enhancing MYC degradation (PI3K inhibition) and blocking MYC production (inhibition of MYC transcription via BRD4 inhibition). MYC inhibition is an important oncology outcome of this new anticancer paradigm because inactivation of MYC down-regulates immuno-oncology targets CD47 and PD-L1. This down-regulation offers a novel immune-oncology approach alone or in combination with checkpoint inhibitors.

SF2523 has arisen from SignalRx’s platform technology for cancer therapeutics that enables the engineering of one small molecule to inhibit two or more molecular targets in the cancer and stromal cell for maximum anticancer efficacy and unprecedented safety in vivo. While most anti-cancer drugs are made with a single cancer target in mind, the lead compound SF2523 was designed to inhibit two or more key orthogonal signaling biomolecules simultaneously within the cancer cell.

The cancer targets for this new technology approach are selected based on forward genetics and the discovery of important cancer synthetic lethalities for therapeutic exploitation. This effective engineering approach is in contrast to the industry paradigm which relies on random screening efforts of large collections of compounds hoping to find interesting dual-target activities. With SignalRx’s technology, it is possible now to molecularly design dual and triple inhibitory chemotypes for maximum in vivo antitumor activity while maintaining a safety advantage over using combinations of drugs to attempt similar attacks on cancer targets.

SignalRx is seeking a partner to accelerate the development of SF2523 and SF2535 into first-in-man clinical trials based on the promising profile of its PI3K/BRD4 inhibitors shown so far. Since these are single molecules with a single PK/PD and toxicity profile, there is a great opportunity to develop them as single therapeutics and streamline their development in combination therapies focused on companion diagnostics built around synthetic lethality discoveries in human cancers such as kinome adaptation mediated by BRD4.